Abstract
10089 Background: The antitumor activity of histone deacetylase inhibitors (HDACI) on multidrug-resistant sarcoma cell lines has never been previously described. Methods: We treated chemotherapy-resistant osteosarcoma and chondrosarcoma cell lines with PCI-24781 in combination with chemotherapeutic agents. MTT assay was used to measure relative inhibition of cell growth in each of the conditions. Western blot analysis was used to determine changes in RAD51 and GADD45α levels as a result of treatment with PCI-24781. Caspase activity was measured with the Apo-One Homogeneous Caspase 3/7 assay kit (Promega Corporation). Results: Four multidrug-resistant sarcoma cell lines treated with HDACI PCI-24781 resulted in dose-dependent accumulation of acetylated histones, p21 and PARP cleavage products. Growth of these cell lines was inhibited by single agent PCI-24781 at IC50 of 0.43 to 2.7 μM. When we looked for synergy of PCI-24781 with chemotherapeutic agents, we found that PCI-24781 reverses drug resistance in all four multidrug resistant sarcoma cell lines and synergizes with chemotherapeutic agents to enhance caspase-3/7 activity. Expression of RAD51 (a marker for DNA double-strand break repair) was inhibited and the expression of GADD45α (a marker for growth arrest and DNA-damage) was induced by PCI-24781 in multidrug resistant sarcoma cell lines. Conclusions: HDACI PCI-24781 synergizes with chemotherapeutic drugs to induce apoptosis and reverses drug resistance in multidrug-resistant sarcoma cell lines. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics
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